tbuckley/cabot-search huggingface dataset:
Final survival results of ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in previously untreated HER2 positive esophago gastric adenocarcinoma: The randomized AIO INTEGA trial.
Authors: Joseph Tintelnot, Alexander Stein, Lisa Paschold, Eray Goekkurt, Christoph Schultheiß, Peter C. Thuss-Patience, Sylvie Lorenzen, Thomas Jens Ettrich, Jorge Riera Knorrenschild, Lutz Jacobasch, Stefan Kubicka, Salah-Eddin Al-Batran, Anke C. Reinacher-Schick, Daniel Pink, Marianne Sinn, Udo Lindig, Axel Hinke, Susanna Hegewisch-Becker, Mascha Binder
Journal: Journal of Clinical Oncology (2023)

4026 Background: In metastatic esophagogastric adenocarcinoma (EGA), the addition of PD-1 inhibitors (i) to chemotherapy has improved the outcome in selected patient populations. The randomized INTEGA trial investigated trastuzumab and PD-1i with FOLFOX or CTLA-4i in 1 st line treatment of advanced HER2+ EGA. Methods: Patients with previously untreated, metastatic HER2+ (local IHC3+ or 2+/ISH+) EGA, and adequate organ function were randomized to trastuzumab and nivolumab (1mg/kg Q3W x4 /240mg Q2W for up to 12 months) in combination with ipilimumab (3mg/kg x4 Q3W; Ipi arm) or mFOLFOX6 (FOLFOX arm) accompanied by a large translational program. The primary endpoint was the 12month overall survival (OS) rate. The trial was registered at ClinicalTrials.gov, NCT03409848. Results: Between March 2018 and May 2020, 97 patients were enrolled and 88 randomized across 21 German sites with the following baseline characteristics: female/male 18/70, median age 60.5 (range 41-80), ECOG 0/1 54/34, GEJ/stomach 66/22. Central post hoc biomarker analysis on 82 evaluable patients showed PD-L1 CPS≥1/≥5 in 59/46 patients and confirmed HER2 (central IHC3+ or 2+/ISH+) positivity in 77 patients. The observed OS rate at 12 months was 70% (95% confidence interval (CI) 54-81%) in the FOLFOX arm, and 57% (95% CI 41-71%) in the Ipi arm. The progression free survival was 10.7 and 3.2 months, and the overall response rate was 53.5% and 34% in the FOLFOX and the Ipi arm, respectively. Although these data are in favor of the FOLFOX arm, the overall survival curves crossed with increased follow-up (median follow-up of 18.8 months) and thus the final median OS was 22.1 and 23.3 months, numerically favoring the Ipi arm. According to the centrally assessed CPS the OS was: 22.1 and 32.2 months in the CPS&lt;5 group, and 22.7 and 12.6 months in the CPS≥5 group for the FOLFOX and the Ipi arm, respectively. Notably, the median tumor burden calculated as the sum of target lesions was numerically lowest in the Ipi arm with higher than median OS. Conclusions: In contrast to limited short term efficacy of the Ipi arm as reflected by the lower PFS, the Ipi arm showed favorable OS, that was inversely correlated to the CPS status. Further analysis of baseline clinical and molecular data to better identify the subgroup of patients benefitting the most of trastuzumab/nivolumab/ipilimumab will be presented at the meeting. Clinical trial information: NCT03409848 . [Table: see text]
Outcomes with bendamustine lymphodepletion prior to brexucabtagene autoleucel for mantle cell lymphoma.
Authors: Elise A. Chong, James N. Gerson, Sunita Dwivedy Nasta, Daniel J Landsburg, Stefan K. Barta, Jakub Svoboda, Elizabeth Weber, Emeline R. Chong, Stephen J. Schuster
Journal: Journal of Clinical Oncology (2023)

e19540 Background: Brexucabtagene autoleucel (brexu-cel) is approved for relapsed/refractory mantle cell lymphoma (MCL). Cyclophosphamide/fludarabine for lymphodepletion (LD) is standard LD prior to brexu-cel. Due to a recent fludarabine shortage as well as institutional practice, we have utilized alternatives to fludarabine-based LD prior to brexu-cel, predominantly bendamustine. Bendamustine is an attractive option because it is included in the label for another anti-CD19 CAR T cell product. We report our institutional experience with bendamustine LD followed by brexu-cel. Methods: We retrospectively examined our institutional records for all patients with MCL who were treated with bendamustine LD followed by brexu-cel from 2020-2022. Progression-free survival (PFS) was analyzed with Kapalan-Meier survival analysis. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: 16 patients received bendamustine followed by brexu-cel. Median age was 65 years (range: 54-76). Median number of prior therapies was 3 (range: 3-8). All patients (100%) had received a BTK inhibitor prior to brexu-cel. 14/16 (88%) received bridging therapy. 14/16 (88%) patients had CRS; 11/14 (79%) had grade 1-2 CRS and 3 (21%) had grade 3 or greater CRS. 5 (31%) patients had ICANS; 2 (40%) had grade 1-2 ICANS, and 3 (60%) had grade 3 or greater ICANS. 10 (63%) patients received tocilizumab, 8 (50%) received dexamethasone, and 3 (19%) received anakinra for management of CRS and/or ICANS. Best objective response rate (ORR) was 81% with 11 (69%) patients achieving CR. Median follow-up was 13.4 months. Estimated 6-month progression-free survival was 86% (95%CI: 54-96%) and 12-month progression-free survival was 63% (95%CI: 32-82). Conclusions: Bendamustine LD prior to brexu-cel for MCL is feasible, and, although these numbers are small, appears to have comparable outcomes to that reported in real world brexu-cel data (best ORR 90% with 82% CR rate, 6 month PFS estimate 69%, 12 month PFS estimate 59%; Y Wang et al. J Clin Oncol 2023) and ZUMA-2 outcomes (93% ORR with 67% CR rate, 12 month PFS estimate 61%; M Wang et al. NEJM 2020).
Efficacy of subsequent therapies in patients (pts) with advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial according to whether disease progression occurred during or after the end of olaparib (ola) maintenance.
Authors: Philipp Harter, Marie-Ange Mouret-Reynier, Domenica Lorusso, Claire Cropet, Eva M. Guerra, Pia Wolfrum-Ristau, Takashi Matsumoto, Ignace Vergote, Nicoletta Colombo, Johanna Unelma Maenpaa, Coriolan Lebreton, Nikolaus de Gregorio, Anna Maria Mosconi, Maria Jesús Rubio-Pérez, Hugues Bourgeois, Peter A. Fasching, Anne-Claire Hardy-Bessard, Dominik Denschlag, Eric Pujade-Lauraine, Isabelle Laure Ray-Coquard
Journal: Journal of Clinical Oncology (2023)

5550 Background: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance ola (a PARP inhibitor) + bevacizumab (bev) led to prolonged progression-free and overall survival vs placebo (pbo) + bev in AOC pts, specifically those with homologous recombination-deficient (HRD+) tumors (Ray-Coquard et al. ESMO 2022, LBA29). Here, we explore the efficacy of subsequent chemotherapy (CT) in pts after progression on first-line (1L) treatment in PAOLA-1. Methods: The efficacy of subsequent CT was explored by analyzing the median time from first subsequent therapy (FST) to second subsequent therapy (SST). Efficacy was compared by FST type, HRD status, and timing of progression (during/after ola). A multivariate Cox model was used in ola + bev pts to identify prognostic factors influencing time from FST to SST, including HRD status, platinum-free interval (PFI), clinical risk based on disease stage and surgical status, timing of progression, and response to 1L CT. All P values are exploratory. Results: In total, 544/806 (67.5%) pts progressed and received subsequent CT: 338/537 (62.9%) ola + bev pts and 206/269 (76.6%) pbo + bev pts. In the overall population and in the subgroup who received platinum-based combination therapy (PBC), time from FST to SST was shortest in pts who progressed during ola (Table). Pts who progressed after ola had similar outcomes to pbo + bev pts (Table). Efficacy was broadly consistent regardless of HRD status (Table). The multivariate analysis confirmed that progression after (vs during) ola prolonged time from FST to SST (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.50–0.84; P=0.0011) independently of other known prognostic factors, such as PFI ≥12 vs &lt;12 months (HR 0.38, 95% CI 0.29–0.51; P&lt;0.0001) or lower vs higher clinical risk (0.58, 0.42–0.81; P=0.0015). Conclusions: In this post hoc exploratory analysis of PAOLA-1, the efficacy of subsequent CT at relapse appeared dependent on whether progression occurred during or after the end of ola treatment. Efficacy was reduced when relapse occurred during ola but was comparable between pts who progressed after ola vs pbo + bev pts. Clinical trial information: NCT02477644 . [Table: see text]
Ten-year outcomes of hypofractionated (45 Gy in 9 fractions) intensity-modulated radiotherapy for localized prostate cancer.
Authors: Sijin Zhong, Yueping Liu, Hui Fang, Ping Tang, Jianrong Dai, Jianzhong Shou, Yexiong Li
Journal: Journal of Clinical Oncology (2023)

e17100 Background: We reported 10-year outcomes of localized prostate cancers treated with hypofractionated intensity-modulated radiotherapy of 45 Gy in 9 consecutive fractions. Methods: From October 2011 to April 2017, thirty patients with localized prostate cancer were enrolled in this prospective trial. The median age of the patients was 72.5 years. According to NCCN recurrence risk criteria, eight patients were at low risk group, 17 at intermediate risk group, 5 at high risk group. All patients were treated with hypofractionated intensity-modulated radiotherapy (IMRT) of 45 Gy in 9 consecutive fractions to their prostate with or without seminal vesicles. Before radiotherapy, three gold fiducials were implanted into the prostate. In order to reduce the rectal high dose irradiation volume , an inflated rectal balloon was placed in the rectum at simulation and every treatment and patients were treated with comfortable full bladder. Static Intensity-modulated radiotherapy (SIMRT) was applied in 1 patient, Volumetric Modulated Arc Therapy (VMAT) in 27 patients, and tomotherapy in 2 patients. Image guided radiotherapy (IGRT) with gold fiducial registration was adopted. Twenty-six patients also received androgen deprivation therapy (ADT). The median time of ADT was 6 months. Progression⁃free survival(PFS) and overall survival(OS) were analyzed using Kaplan-Meier analysis. All grade ≥1 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 5.0 (CTCAE 5.0) and Radiation Therapy Oncology Group (RTOG) late morbidity criteria , and GU and GI toxicities were cumulatively calculated. Results: After a median follow-up of 102 months (65~131 months), the 10-year OS was 90.0%(95% confidence interval, 83.3%-96.7%), and the 10-year PFS was 86.5% (95% confidence interval, 79.1%-93.9%). According to CTCAE 5.0, grade 1 acute gastrointestinal (GI) toxicity developed in 12 patients, grade 2 in 2 patients, grade 3 in 2 patients, and grade 1 acute genitourinary (GU) toxicity developed in 12 patients, grade 2 in 2 patients, and no grade 3 or higher toxicity occurred. According to RTOG late morbidity criteria, late (≥3 months after radiotherapy) grade 1 GI toxicity developed in 4 patients (13.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%), and late grade 1 GU toxicity occurred in 1 patient (3.3%), grade 2 in 1 (3.3%), grade 3 in 1 (3.3%). No grade 4 or higher GI and GU toxicities developed. Only one grade 3 GI and one grade 2 GU toxicities were observed for the maximum toxicity at the last follow-up. The potency was not evaluated. Conclusions: The 10-year oncologic outcomes of this shortened hypofractionated IMRT regimen for mainly low/intermediate risk prostate cancer patients is favorable with acceptable acute and late toxicities.
Circulating ether lipids in prostate cancer.
Authors: Lisa Horvath, Hui-Ming Lin, Kevin Huynh, Thomas Meikle, Anthony M. Joshua, Arun Azad, Winston Tan, Lisa Butler, Peter Meikle
Journal: Journal of Clinical Oncology (2023)

e17009 Background: Decreased circulating levels of ether lipids (glycerophospholipids with an ether-linked fatty alcohol, e.g. plasmalogens) have been observed in obesity, diabetes and cardiovascular disease. In vitro and in vivo studies suggest that ether lipids are anti-inflammatory and protective against obesity. A recent landmark study revealed that ether lipids can kill cancer cells through ferroptosis. However, the role of ether lipids in prostate cancer has not been thoroughly investigated despite the known association of dysregulated lipid metabolism with poorer clinical outcomes. The aim of this study was to assess the relationship between the circulating profiles of ether lipids and clinical outcomes in localised and metastatic prostate cancer. Methods: The profiles of ~150 ether lipids (8 lipid classes) in plasma lipidomic data from localised prostate cancer (389 men in Australia) and metastatic castration-resistant prostate cancer (mCRPC)(2 cohorts –147 men in USA, 128 men in Australia) were analysed for associations with disease progression or overall survival (OS). Open-access genomic data of mCRPC tumours (108 men, CbioPortal) were analysed for aberrations in genes associated with ether lipid metabolism in relation to clinical outcome. Results: Previously in these study cohorts, we had identified men with poorer prognosis based on their plasma lipidome and our validated sphingolipid signature. These men with poorer prognosis have lower plasma levels of ether lipids than those with better prognosis (t-test p &lt; 0.05, localised disease – 110 ether lipids, mCRPC – 54 ether lipids). Decreased plasma levels of up to 46 ether lipid species were associated with higher rates of clinical relapse in localised disease (hazard ratio (HR) range 0.37-0.73, p-value range 0.006-0.049), shorter radiological progression-free survival in mCRPC (HR range 0.35-0.73, p-value range 0.00009-0.049), and shorter OS in mCRPC (HR range 0.33-0.79, p-value range 0.000004-0.0497). Chromosomal loss of tumour GNPAT, an essential gene in ether lipid synthesis, was associated with shorter OS in mCRPC (HR = 1.36, 95% CI 1.02-1.81, p = 0.03). Conclusions: Lower circulating levels of ether lipids were associated with worse prognosis in localised and metastatic prostate cancer, suggesting that these lipids are protective against disease progression. Further research is required to understand the role of ether lipids in disease progression, and to determine if modulation of ether lipid levels through supplementation is beneficial.
Approaches and data needed for real-world evaluation of multicancer early detection tests.
Authors: Sean Tunis, Mahesh K. B. Parmar, Howard A. Burris, Michelle M. LeBeau, Larry Kessler
Journal: Journal of Clinical Oncology (2023)

e15069 Background: The MCED Consortium is a group of volunteers, advisors, and companies from the US and the UK spanning a wide range of expertise in biomarker evaluation and implementation, with a special focus on clinical practice, health equity, and communication. The development of Multi Cancer Early Detection (MCED) markers may herald a new approach to screening and detection of multiple cancers at one time via various biological assays. Methods: The Consortium is developing recommendations for the evaluation of test utility, appropriate population targets for screening or early detection, downstream actions in health systems, issues of health equity, and communication challenges related to this new, potentially revolutionary generation of tests. While randomized controlled trials with cancer-specific endpoints have been the gold standard for the evaluation of cancer screening tests for decades, and have successfully shown effectiveness of breast, colorectal, cervical and lung cancer screening, there are compelling reasons not to rely entirely on those approaches to guide the evaluation and clinical use of MCEDs. Results: A large number of MCED products are likely to reach the market well before trials with mortality endpoints can be completed. The release of tests in clinical practice in the US via the laboratory-developed-test pathway means data could be available many years before data is available from trials. The MCED Consortium proposes approaches for the structure, systematic collection of real-world data that will complement such trials. This includes adopting shared definitions of RWD &amp; RWE, definition of core data elements to be collected from all patients undergoing MCED testing, and the need for collaboration strategies across test developers, health systems, payers, clinicians, and others. Conclusions: We will present a framework for learning from clinical experience through data collection that will move MCEDs forward in the context of sensible clinical practice.
Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis?
Authors: Lifeng Sun, Yuyan Zheng, Chao Chen, Zhiyuan Gong
Journal: Journal of Clinical Oncology (2023)

3619 Background: Previous studies have shown that T4 stage was one of the risk factors for peritoneal metastasis (PM) of colorectal cancer (CRC). However, there is paradoxical data to prove that prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) treatment is beneficial for CRC patients. Methods: In this cohort study, 220 consecutive CRC patients with T4N0-2M0 were enrolled and recorded from November 2014 to November 2018 with a 3-year follow-up following surgery. A propensity score matching (PSM) approach was applied to balance the clinicopathological characteristics. Finally, 180 patients were matched successfully to further analyze. The 3-year disease-free survival (DFS) was set as the primary outcome, and the PM rate between the two groups after PSM was analyzed. Results: Before PSM, of 220 CRC patients enrolled, the 3-year DFS was 83.9% in the HIPEC group, which was better than 67.2% in the control group. The cumulative PM incidence was 2.2% in the HIPEC group and 12.6% in the control group (p = 0.047). After PSM, 180 matched patients were formed for further analysis. The DFS and the cumulative PM rate of the patients in the HIPEC group were also better than that in the control group (p = 0.034 and 0.047, respectively). For laparoscopic surgery subgroup analyses, PM rate of the patients with laparoscopic surgery was 13.8% in the No HIPEC group, and 2.6% in the HIPEC group (p = 0.070). Through multivariable analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.19-0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95% CI 1.09-3.56; p = 0.025]. Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2% in the HIPEC group and 0.7% in the control group (p = 0.439). Conclusions: Prophylactic HIPEC may improve the prognosis in the patients with T4N0-1M0 CRC, but not in the T4N2M0 CRC, and it does not significantly increase the surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC is relatively safe, which does not increase the risk of PM.
Sequential therapy versus first-line tyrosine kinase inhibitor plus immune checkpoint inhibitor therapy for unresectable hepatocellular carcinoma.
Authors: Minghao Ruan, Cheng Yang, Jing Zhao, Kangkang Zhi, Xiaochen Feng, Jin Zhang, Riming Jin, Yao Li, Dong Wu, Hui Liu, Wen Sun, Ruoyu Wang
Journal: Journal of Clinical Oncology (2023)

e16122 Background: The treatment landscape of hepatocellular carcinoma (HCC) evolves, but the optimal sequential strategy for tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI)-based combination therapy is still unclear. This study compared the outcome and efficacy of TKI-(TKI+ICI) sequential therapy versus first-line TKI+ICI combination therapy in unresectable HCC. Methods: The patients who had received TKI (lenvatinib or sorafenib) plus ICI (anti-PD-1/PD-L1 monoclonal antibody) as first-line therapy or TKI-(TKI+ICI) sequential therapy were retrospectively included. Treatment efficacy (progression-free survival (PFS) and overall survival (OS)) to sequential therapy or TKI+ICI combination therapy as well as treatment-related adverse events (TRAEs) were assessed. Results: Among 392 patients included, 55 underwent TKI-(TKI+ICI) sequential therapy and 337 underwent first-line TKI+ICI combination therapy. The median PFS was significantly longer in TKI-(TKI+ICI) group than that in TKI+ICI group (16.2 months versus 7.7 months, HR 0.65 [0.47-0.90]; p=0.009). The median OS was not reached in TKI-(TKI+ICI) group and was 22.8 months in TKI+ICI group (HR 0.53 [0.33-0.83]; p=0.006). Multivariate analyses revealed that Child- Pugh score, BCLC stage and sequential therapy were independently associated with PFS. Child-pugh score, macrovascular invasion (MVI), AFP levels and sequential therapy were independently associated with OS. Subgroup analysis indicated that patients with younger age, male gender, an ECOG PS 1, Child-Pugh score A, HBV(+), HCV(-), BCLC stage C, presence of MVI or extrahepatic metastasis could remarkably benefit from sequential therapy. The survival outcome and objective response to TKI+ICI combination therapy was comparable between groups. The incidence of TRAEs were slightly higher in TKI-(TKI+ICI) group ( p=0.022), but the difference was not significant for Grade≥3 events ( p=0.126). Conclusions: TKI-(TKI+ICI) sequential therapy is a valid therapeutic strategy for patients with HCC compared with first-line TKI+ICI combination therapy.
Role of immune checkpoint inhibitors in PDL1-negative, low TMB, stable MSI metastatic solid tumours: Single centre study.
Authors: Vijay Moorthy, Sharafudheen T P, Delvin Kumar, Roshni Dasgupta, Mohammed Naseer, Srinivas B.J, Priyank Tripathi, Naik Radheshyam, Shekar Patil, Satheesh Chiradoni Thungappa, Madhu Nagaraj, Sajad Munaf, Srinivas Naidu, Mansi Shah, Niyati Prakash Sanghavi, Ravi Thippeswamy, Adithya krishna S, Spoorthi Reddy, Goutham Kumar, Abhijna Vithal Yergolkar
Journal: Journal of Clinical Oncology (2023)

e14603 Background: Immune check point inhibitors clearly play a part in malignancies with elevated PDL1 expression, high TMB or unstable MSI. There is no information on PDL1 negative, low TMB/MSI stable metastatic solid tumours, however several treatment trials advise using immune check point inhibitors regardless of tissue agnostic indicators. Detailed subset analysis was not performed, though. This study examines the effectiveness of immunotherapy in metastatic solid tumours with PDL1 negative/TMB low/MSI stability. Methods: Study was carried out from Jan-2020 to Dec- 2022 (retrospective data from 2019 also included for analysis). Inclusion criteria: Metastatic solid tumours in patients who received immunotherapy. Exclusion criteria: PDL1&gt;1% ( Either TPS/ CPS &gt;1) by sp263 or 22c3 platforms, TMB&gt; 10, Unstable MSI by IHC or by genomics. Patients who were diagnosed with melanoma, hepatocellular cancer, renal cell carcinoma were also excluded from the study. Response was initially assessed after 3 to 6 cycles of immunotherapy, analysed by PET CT scan. Data were analysed using standard statistical method. Results: After carefully applying exclusion criteria, a total of 40 patients were enrolled in the research, with a male to female ratio of 1.5. Overall response rate in all tumours was 17.5% (7/ 40) Immune checkpoint inhibitors' ORRs at various tumour locations. Among the responders head and neck tumours 2/4 (50%) and lung cancers (37.5%) had higher ORR who also had greater depth of response, living more than 2 years from diagnosis. There is no response observed in gastroesophageal (0/8) gynaecological malignancies (clear cell ovary (0/2), endometrial and cervical (0/3). A patient with urothelial carcinoma who also had a BRCA mutation and was one out of seven responded to IO. Conclusions: Regardless of the presence of PDL1 expression, high TMB, or MSI, adding immune checkpoint inhibitors to the treatment regimen for metastatic head and neck malignancies and lung tumours that lack driver mutations is obviously advantageous. On the other hand, immunotherapy had no effect on gastrointestinal, gynaecological, or urothelial tumours. To validate these findings, more research with several centres and a sizable sample size is necessary. It's interesting that one patient responded to immunotherapy with positive BRCA mutation. Investigating immunotherapy in HRR deficient tumours may shed further insights. [Table: see text]